Computational Repurposing of Relatively Large Drugs for the Receptor Binding Domain of SARS‐CoV‐2 Spike Protein
Mansour H. Almatarneh, Ahmad M. Alqaisi, Amani N. Al‐Shanti, Abd Al‐Aziz A. Abu‐Saleh, Mohammed S. Al‐Sheraideh, Yuming Zhao, Kabir M. Uddin · ChemistrySelect · 2025
Abstract Currently, therapeutic options for COVID‐19 remain limited. While drug repurposing offers a rapid strategy to address this gap, most studies focus on small molecules, overlooking larger drugs (>500 Da) that may exhibit optimized pharmacokinetics and translational potential. Here, we computationally repurpose FDA‐approved large drugs (MW > 500, LogP ≤ 5) targeting the receptor‐binding domain (RBD) of the SARS‐CoV‐2 spike protein. Through molecular docking, molecular dynamics (MD) simulations (100 ns), and binding energy calculations, we prioritized candidates with high affinity for the RBD. Notably, Atazanavir, Valrubicin, Telotristat, and Clotrimazole (identified here) interact with hotspot residues critical for ACE2 binding, suggesting a mechanism to disrupt viral entry. While our findings align with experimental mutagenesis data, they also highlight underexplored opportunities in large‐drug repurposing. This work provides a focused candidate list for experimental validation, complementing existing literature by broadening the scope of actionable targets.